Summary
A bioRxiv preprint reports that reducing the catalytic activity of immunotoxin payloads improved selectivity between receptor-high and receptor-low cells. In an in vivo HER2-targeted test, the attenuated version had a 400-fold higher maximum tolerated dose than its wild-type counterpart.
A preclinical study posted on bioRxiv on 2 October 2026 reports that reducing the catalytic activity of immunotoxin payloads can improve their selectivity. The researchers compared immunotoxins targeting CD123, HER3 and HER2, and found that tuning toxin activity to match receptor engagement mattered more for distinguishing receptor-high from receptor-low cells than increasing receptor-binding affinity or avidity alone.
Matching targeting to toxin activity
Immunotoxins combine a receptor-binding component with a bacterial toxin payload that acts inside cells. The targeting component helps direct the toxin to cells carrying a chosen receptor. But, as the preprint’s abstract notes, even limited uptake can kill receptor-low cells when the payload is exceptionally potent, restricting the dose that can be given safely.
The researchers varied the binding properties of the receptor-binding domain and the catalytic activity of the toxin payload. They report that increasing binding affinity or avidity changed potency but offered limited control over selectivity between receptor-high and receptor-low cells. Attenuating catalytic activity produced larger gains in selectivity when the remaining payload activity was appropriately matched to receptor engagement. The optimal degree of attenuation varied with both the receptor and the toxin scaffold.
Affinity describes the strength of an individual binding interaction; avidity describes the combined strength of multiple interactions. The findings point to a design trade-off: stronger targeting or greater toxin activity is not necessarily better on its own. The balance between how much payload reaches a cell and how actively it works can shape the difference between killing target cells and harming cells with lower receptor levels.
In vivo result with HER2-targeted immunotoxin
In an in vivo test of a HER2-targeted immunotoxin, the authors report that attenuating the payload increased the maximum tolerated dose 400-fold. The attenuated version also showed robust antitumour activity at doses below its toxicity limit. The wild-type, or unattenuated, counterpart showed no detectable efficacy at tolerated doses in that comparison.
The work is a bioRxiv preprint describing preclinical experiments, not a clinical study. Its abstract does not state the in vivo model or sample sizes, so the reported dose difference applies to the experimental system studied and cannot be read as a human dose estimate. The authors disclose that they have filed provisional patents related to the work.